JP2004528314A - Rho kinase inhibitor - Google Patents

Rho kinase inhibitor Download PDF

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JP2004528314A
JP2004528314A JP2002576235A JP2002576235A JP2004528314A JP 2004528314 A JP2004528314 A JP 2004528314A JP 2002576235 A JP2002576235 A JP 2002576235A JP 2002576235 A JP2002576235 A JP 2002576235A JP 2004528314 A JP2004528314 A JP 2004528314A
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rho kinase
acid
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JP4320705B2 (en
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ナガラスナム，ダナパラン
ワン，チュングアン
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Bayer Corp
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Abstract

化合物およひその誘導体、それらの合成、およびＲｈｏキナーゼ阻害剤としてそれらの使用が開示される。本発明のこれらの化合物は腫瘍発育の阻止、勃起不全の処置、およびＲｈｏキナーゼによって仲介される他の適応症、例えば冠心疾患の処置のために有用である。Compounds and their derivatives, their synthesis, and their use as Rho kinase inhibitors are disclosed. These compounds of the present invention are useful for inhibiting tumor growth, treating erectile dysfunction, and other indications mediated by Rho kinase, such as coronary heart disease.

Description

【技術分野】
【０００１】
本出願は２００１年３月２３日に出願された米国仮出願Ｎｏ．６０／２７７，９７４および２００１年８月２９日に出願された米国特許出願Ｎｏ．６０／３１５，３３８の出願日の利益を主張する。
【０００２】
本発明は化合物、その誘導体、それらの合成、およびＲｈｏキナーゼ阻害剤としてそれらの使用に関する。本発明のこれらの化合物は腫瘍発育阻止、勃起不全の処置、およびＲｈｏキナーゼによって仲介される他の適応症、例えば冠心疾患の処置に有用である。
【背景技術】
【０００３】
高血圧、勃起不全、冠大脳循環障害、神経退化障害およびがんを含む多数のヒトおよび動物病の病理学は、アクチン細胞骨格の変化に直接結びつけることができる。これらの病気は重大な満たされない医学的必要性を提供する。アクチン細胞骨格はすべての真核細胞に見られるアクチンフィラメントの網とアクチン結合タンパクから構成されている。平滑筋細胞においては、アクチン細胞骨格の集合および離散が平滑筋収縮および弛緩に責任ある一次的原動力である。非平滑筋細胞においては、アクチン細胞骨格の動的再配置が細胞形態、細胞移動性、アクチンストレス線維生成、細胞接着、および軸索収縮、ファゴサイト−シスもしくは細胞分裂のような特化された細胞機能の調節に責任がある（Ｖａｎ Ａｅｌｓｔ，ｅｔ ａｌ．Ｇｅｎｅｓ Ｄｅｖ １９９７，１１，２２９５）。
【０００４】
アクチン細胞骨格はＲａｓスーパーファミリーのサブセットであるタンパクのファミリーによってコントロールされる。このサブセットは現在ＲｈｏＡないしＧとＲｈｏＧ（集合的にＲｈｏと呼ばれる）、Ｒａｃ１および２，Ｃｄｃ４２ＨｓおよびＧ２５ＫおよびＴＣ１０イソフォームよりなる（Ｍａｃｋａｙ，ｅｔ ａｌ．Ｊ Ｂｉｏ Ｃｈｅｍ １９９８，２７３，２０６８５）。これら３種のタンパクは固有のＧＴＰアーゼ活性を持つＧＴＰ（グアニンヌクレオチドトリフォスフェート）結合タンパクである。それらは分子スイッチとして作用し、そして結合したＧＤＰ（グアニンヌクレオチドジフォスフェート）とそして活性ＧＴＰ結合状態の間をサイクルにする。生化学的および遺伝子操作を使用して、各ファミリーメンバーに機能を割当てることが可能になった。活性化した時Ｒｈｏタンパクはアクチンストレス線維とアクチンフィラメントの厚い束の生成、そして焦点の接着コンプレックスにおいてインテグリンのクラスター化を制御する。活性化した時Ｒａｃタンパクは細胞表面上の膜波打ちの生成を制御し、そしてＣｄｃ４２は糸状足生成を制御する。合同してこれらタンパクファミリーは細胞運動、軸索誘導、細胞分裂、そして細胞形態、形状および極性の変化を含む、キー細胞機能の制御において重要な役割を果す。
【０００５】
細胞のタイプおよび活性化レセプターに応じて、Ｒｈｏタンパクは様々の生物学的応答を制御することができる。平滑筋細胞においては、Ｒｈｏタンパクは平滑筋収縮の間カルシウム感作に責任がある。非平滑筋細胞においては、Ｒｈｏ ＧＴＰアーゼはリソフォスファチジン酸（ＬＰＡ）、トロンビンおよびトロンボキサンＡ2のようなアゴニストに対する細胞応答に対して責任がある（Ｆｕｋｕｄａ，ｅｔ ａｌ．Ｔｒｅｎｄｓ Ｐｈａｒｏｌ Ｓｃｉ ２００１，２２，３２）。アゴニスト応答は、他のレセプターも含まれ得るが、ヘテロトリマーＧタンパク、Ｇアルファ１２またはＧアルファ１３を介して連結される（Ｇｏｅｔｚｌ，ｅｔ ａｌ．Ｃａｎｃｅｒ Ｒｅｓ １９９９，５９，４７３２；Ｂｕｈｌ，ｅｔ ａｌ．Ｊ Ｂｉｏｌ Ｃｈｅｍ １９９５，２７０，２４６８１）。活性化した時Ｒｈｏ ＧＴＰアーゼはＰＩＰ５−キナーゼ、ローセキン、ローフィリン、ＰＫＮおよびＲｈｏキナーゼイソフォームＲＯＣＫ−１／ＲＯＫベーターおよびＲＯＣＫ−１／ＲＯＫアルファを含む多数の下流エファクターを活性化する（Ｍａｃｋａｙ ｅｔ ａｌ．Ｊ Ｂｉｏｌ Ｃｈｅｍ １９９８，２７３，２０６８５；Ａｓｐｅｎｓｔｒｏｍ，Ｃｕｒｒ Ｏｐｉｎ Ｃｅｌｌ Ｂｉｏｌ １９９９，１１，９５；Ａｍａｎｏ，ｅｔ ａｌ．Ｅｘｐ Ｃｅｌｌ Ｒｅｓ ２０００，２６１，４４）。
【０００６】
Ｒｈｏキナーゼはウシ脳から単離されたＲｈｏＡ相互作用タンパクとして同定された（Ｍａｔｓｕｉ，ｅｔ ａｌ．Ｅｍｂｏ Ｊ １９９６，１５，２２０８）。それはタンパクキナーゼの筋ジストロフィーファミリーのメンバーであり、そしてアミノ末端においてセリン／スレオニンドメインと、中央領域においてコイル巻きドメインと、そしてカルボキシ末端においてＲｈｏ相互作用ドメインを含んでいる（Ａｍａｎｏ，ｅｔ ａｌ．Ｅｘｐ Ｃｅｌｌ Ｒｅｓ ２０００，２６１，４４）。そのキナーゼ活性はＧＴＰ結合ＲｈｏＡへ結合する時増強され、そして細胞へ導入される時それは活性化ＲｈｏＡの多数の活性を再現する。平滑筋細胞においては、Ｒｈｏキナーゼはカルシウム感作および平滑筋収縮を仲介し、Ｒｈｏキナーゼの阻害は筋収縮によって誘発された５−ＨＴおよびフェニレフリンアゴニストをブロックする。非平滑筋細胞へ導入された時、Ｒｈｏキナーゼはストレス線維生成を誘発し、そしてＲｈｏＡによって仲介される細胞形質転換のために必要である（Ｓａｈａｉ，ｅｔ ａｌ．Ｃｕｒｒ Ｂｉｏｌ １９９９，９，１３６）。Ｒｈｏキナーゼは、フォスフォリル化によりミオシン軽鎖（Ｓｏｍｌｙｏ，ｅｔ ａｌ．Ｊ Ｐｈｙｓｉｏ（Ｌｏｎｄ）２０００，５２２ ｐｔ２，１７７）、ミオシン軽鎖フォファターゼ結合サブユニット（Ｆｕｋａｔａ，ｅｔ ａｌ．Ｊ Ｃｅｌｌ Ｂｉｏｌ １９９８，１４１，４０９）、およびＬＩＭ−キナーゼ２（Ｓｕｍｉ，ｅｔ ａｌ．Ｊ Ｂｉｏ Ｃｈｅｍ ２００１，２７６，６７０）を含む多数の下流タンパクを調節する。
【０００７】
動物モデルにおいてＲｈｏキナーゼの阻害はヒト病気のためのＲｈｏキナーゼ阻害剤の多数の利益を証明した。（＋）−トランス−４−（１−アミノエチル）−（ピリジン−４−イルアミノカルボニル）シクロヘキサンジ塩酸塩−水和物（ＷＯ００／０７８３５１，ＷＯ００／０５７９１３）、および置換イソキノリンスルホニル化合物（ＥＰ００１８７３７１）を動物モデルにおいて活性を有するＲｈｏキナーゼ阻害剤としてクレームしているいくつかの特許が見られる。これらは高血圧（Ｖｅｈａｔａ，ｅｔ ａｌ．Ｎａｔｕｒｅ １９９７，３８９，９９０）、動脈硬化（Ｒｅｔｚｅｒ，ｅｔ ａｌ．ＦＥＢＳ Ｌｅｔｔ ２０００，４６６，７０）、再狭窄（Ｅｔｏ，ｅｔ ａｌ．Ａｍ Ｊ Ｐｈｙｓｉｏｌ Ｈｅａｒｔ Ｃｉｒｃ Ｐｈｙｓｉｏｌ ２０００，Ｈ１７４４；Ｎｅｇｏｒｏ，ｅｔ ａｌ．Ｂｉｏｃｈｅｍ Ｂｉｏｐｈｙｓ Ｒｅｓ Ｃｏｍｍｕｎ １９９９，２６１，２１１）、脳虚血症（Ｕｅｈａｔａ ｅｔ ａｌ．Ｎａｔｕｒｅ １９９７，３８９，９９０）；Ｓｅａｓｈｏｌｔｚ，ｅｔ ａｌ．Ｃｉｒｃ Ｒｅｓ １９９９，８４，１１８６；Ｈｉｔｏｍｉ，ｅｔ ａｌ．Ｌｉｆｅ Ｓｃｉ ２０００，６７，１９２９；Ｙａｍａｍｏｔｏ，ｅｔ ａｌ．Ｊ Ｃａｒｄｉｏｖａｓｃ Ｐｈａｍａｃｏｌ ２０００，３５，２０３），脳血管痙れん（Ｓａｔｏ，ｅｔ ａｌ．Ｃｉｒｃ Ｒｅｓ ２０００，８７，１９５；Ｋｉｍ，ｅｔ ａｌ．Ｎｅｕｒｏｓｕｒｇｅｒｙ ２０００，４６，４４０），勃起不全（Ｃｈｉｔａｌｅｙ，ｅｔ ａｌ．Ｎａｔ Ｍｅｄ ２００１，７，１１９），神経退化および脊髄障害のような中枢神経系障害（Ｈａｒａ，ｅｔ ａｌ．Ｊ Ｎｅｕｒｏｓｕｒｇ ２０００，９３，９４；Ｔｏｓｈｉｍａ，ｅｔ ａｌ．Ｓｔｒｏｋｅ ２０００，３１，２２４５），Ｒｈｏキナーゼの阻害が腫瘍細胞生育および転移を阻害することを示した新形成（Ｉｔｏｈ，ｅｔ ａｌ．Ｎａｔ Ｍｅｄ １９９９，５，２２１；Ｓｏｍｌｙｅ，ｅｔ ａｌ．Ｂｉｏｃｈｅｍ Ｂｉｏｐｈｙｓ Ｒｅｓ Ｃｏｍｍｕｎ ２０００，２６９，６５２），脈管形成（Ｕｃｈｉｄａ，ｅｔ ａｌ．Ｂｉｏｃｈｅｍ Ｂｉｏｐｈｙｓ Ｒｅｓ Ｃｏｍｍｕｎ ２０００，２６９，６３３；Ｇｉｎｇｒａｓ，ｅｔ ａｌ．Ｂｉｏｃｈｅｍ Ｊ ２０００，３４８ Ｐｔ ２，２７３），血小板凝集（Ｋｌａｇｅｓ，ｅｔ ａｌ．Ｊ Ｃｅｌｌ Ｂｉｏｌ １９９９，１４４，７４５；Ｒｅｔｚｅｒ，ｅｔ ａｌ．Ｃｅｌｌ Ｓｉｇｎａｌ ２０００，１２，６４５）および白血球凝集（Ｋａｗａｇｕｃｈｉ，ｅｔ ａｌ．Ｅｕｒ Ｊ Ｐｈａｍａｃｏｌ ２０００，４０３，２０３；Ｓａｎｃｈｅｚ−Ｍａｄｒｉｄ，ｅｔ ａｌ．Ｅｍｂｏ Ｊ １９９９，１８，５０１）のような動脈止血障害、喘息（Ｓｅｔｏｇｕｃｈｉ，ｅｔ ａｌ．Ｂｒ Ｊ Ｐｈａｍａｃｏｌ ２００１，１３２，１１１；Ｎａｋａｈａｒａ，ｅｔ ａｌ．Ｅｕｒ Ｊ Ｐｈａｍａｃｏｌ ２０００，３８９，１０３），眼内圧調節（Ｈｏｎｊｏ，ｅｔ ａｌ．Ｉｎｖｅｓｔ Ｏｐｈｔｈａｌｍｏｌ Ｖｉｓ Ｓｃｉ ２００１，４２，１３７），および骨吸収（Ｃｈｅｌｌａｉａｈ，ｅｔ ａｌ．Ｊ Ｂｉｏｌ Ｃｈｅｍ ２０００，２７５，１１９９３；Ｚｈａｎｇ，ｅｔ ａｌ．Ｊ Ｃｅｌｌ Ｓｃｉ １９９５，１０８，２２８５）のような循環器病のモデルを含んでいる。
【０００８】
患者においてＲｈｏキナーゼの阻害はクモ膜下出血後の脳血管痙れんおよび虚血を制御するための利益を有する（Ｐｈａｒｍａ Ｊａｐａｎ １９９５，１４７０，１６）。
【発明の開示】
【０００９】
本発明において提供される化合物およびそれらの誘導体はＲｈｏキナーゼ阻害剤として有用であり、そのため高血圧、動脈硬化、再狭窄、脳虚血病、脳血管痙れん、神経退化、骨髄損傷、乳房、前立腺、大腸、卵巣、脳および肺のがんおよびそれらの転移、止血障害、喘息、緑内障および骨粗しょう症の処理に有用性を有する。
【００１０】
加えて、本発明の化合物は勃起不全、すなわちＲｈｏキナーゼによって仲介される勃起不全を処置するために有用である。勃起不全は性交に適切な勃起を得ることまたは持続することの不可能として定義することができる。ＷＯ９４／２８９０２，Ｕ．Ｓ．Ｐ．６，１０３，７６５およびＵ．Ｓ．Ｐ．６，１２４，４６１参照。
【００１１】
本発明は以下の式の化合物を提供する。
【００１２】
【化１５】

Figure 2004528314
【００１３】
【化１６】
Figure 2004528314
【００１４】
【化１７】
Figure 2004528314
【００１５】
【化１８】
Figure 2004528314
【００１６】
【化１９】
Figure 2004528314
【００１７】
【化２０】
Figure 2004528314
【００１８】
本発明は式Ｉ−VIの薬学的に許容し得る塩にも向けられる。好適な薬学的に許容し得る塩は当業者には良く知られており、そして塩酸、臭化水素酸、硫酸、リン酸、メタンスルホン酸、スルホン酸、酢酸、トリフルオロ酢酸、リンゴ酸、酒石酸、クエン酸、乳酸、シュウ酸、コハク酸、フマル酸、マレイン酸、安息香酸、サリチル酸、フェニル酢酸、およびマンデル酸のような無機酸および有機酸の塩を含む。加えて、薬学的に許容し得る塩は、アルカリカチオン（例えばＬｉ+，Ｎａ+またはＫ+）、アルカリ土類カチオン（例えばＭｇ++，Ｃａ++，またはＢａ++）、アンモニウムカチオンを含んでいる塩のような無機塩基の酸塩、それにトリエチルアミン、Ｎ，Ｎ−ジエチルアミン、Ｎ，Ｎ−ジシクロヘキシルアミン、ピリジン、Ｎ，Ｎ−ジメチルアミノピリジン（ＤＭＡＰ）、１，４−ジアザビシクロ〔２．２．２〕オクタン（ＤＡＢＣＯ）、１，５−ジアザビシクロ〔４．３．０〕ノネンー５（ＤＢＮ）および１，８−ジアザビシクロ〔５．４．０〕ウンデセン−７（ＢＢＵ）のプロトン化またはペルアルキル化から発生するような脂肪族および芳香族置換アンモニウムおよび４級アンモニウムカチオンを含んでいる有機塩基の酸塩を含む。
【００１９】
式Ｉ−VIの化合物の多数は不斉炭素原子を有し、そしてそれ故ラセミ形および光学活性形で存在する。エナンチオマーおよびジアステレオマー混合物の分離方法は当業者には良く知られている。本発明はＲｈｏキナーゼ阻害活性を有する式Ｉ−VIの化合物の単離されたラセミ形または光学活性形のどれも含む。
【００２０】
本発明は、式Ｉ−VIの化合物と、生理学的に許容し得る担体を含んでいる薬剤組成物も含んでいる。
【００２１】
さらに本発明は、式Ｉ−VIの化合物、または式Ｉ−VIの化合物を含む薬剤組成物を投与することにより、Ｒｈｏキナーゼによって仲介される適応症を処置することを含む。このように、本発明は高血圧、動脈硬化、再狭窄、脳虚血症または痙れんのような循環器病、神経退化および脊髄傷害のような中枢神経系障害、勃起不全例えばＰＤＥ−５に対して満足な応答を持たない患者、およびＲｈｏキナーゼによって仲介されるがん（例えば腫瘍生育）に対し、式Ｉの化合物の有効量を例えばそれを必要とする宿主へ投与することによって処置することを含む。Ｒｈｏキナーゼによって仲介されるがんおよび腫瘍は、乳房、大腸、前立腺、卵巣、脳および肺のがんと、それらの転移を含む。
【００２２】
化合物は、投与単位製剤において経口、局所、非経口、吸入またはスプレー、経膣、経腸または舌下的に投与することができる。注射によって投与とは、静脈内、動脈内、筋肉内、皮下および非経口注射と、それに注入技術の使用も含む。皮膚投与は局所的または経皮投与を含み得る。１以上の化合物が１種以上の非毒性の薬学的に許容し得る担体および、もし望むならば、他の活性成分と共に存在し得る。
【００２３】
経口使用を意図する組成物は、薬剤組成物の製造のための任意の適切な既知方法に従って製造することができる。そのような組成物は服用し得る製剤を提供するため、希釈剤、甘味剤、矯味剤、着色剤および保存剤からなる群から選ばれた１以上の剤を含有することができる。錠剤は錠剤の製造に適した非毒性の薬学的に許容し得る補助剤と混合された活性成分を含む。これら補助剤は、例えば、炭酸カルシウム、炭酸ナトリウム、乳糖、リン酸カルシウムまたはリン酸ナトリウムのような不活性希釈剤、造粒剤および崩壊剤、例えばコーンスターチまたはアルギン酸、および結合剤、例えばステアリン酸マグネシウム、ステアリン酸またはタルクである。錠剤は未被覆か、または消化管内において崩壊および吸収を遅らせ、それによって長時間に亘って被覆することができる。例えば、グリセリルモノステアレートまたはグリセリルジステアレートのような時間遅延材料を使用することができる。これら化合物は固形の速放性形にも調製することができる。
【００２４】
経口使用のための製剤は硬ゼラチンカプセルとしても提供することができ、その場合は活性成分は不活性の固体希釈剤、例えば炭酸カルシウム、リン酸カルシウムまたはカオリンと混合され、または活性成分が水または油性媒体、例えばピーナッツ油、液状パラフィンもしくはオリーブ油と混合される軟ゼラチンカプセルとして提供することもできる。
【００２５】
水性懸濁液の製造のために適した補助剤との混合物に活性成分を含んでいる水性懸濁液も使用することができる。そのような補助剤は懸濁剤、例えばカルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシプロピルメチルセルロース、アルギン酸ナトリウム、ポリビニルピロリドン、トラガントガムおよびアラビアガムであり、分散剤もしくは湿潤剤は天然フォスファチド例えばレシチン、または脂肪酸のアルキレンオキサイド縮合物例えばポリオキシエチレンステアレート、または長鎖脂肪族アルコールとのアルキレンオキサイド縮合物例えばヘプタデカエチレンオキシセタノール、またはポリオキシエチレンソルビトールモノオレエートのような脂肪酸とヘキシトールから誘導された部分エステルのアルキレンオキシド縮合物、または脂肪酸とヘキシトール無水物から誘導された部分エステルのアルキレンオキシド縮合物例えばポリオキシエチレンソルビタンモノオレエートであることができる。水性懸濁液はまたは１種以上の保存剤例えばｐ−ヒドロキシ安息香酸エチルもしくはｎ−プロプルエステル、１種以上の着色剤、１種以上の矯味剤、およびショ糖もしくはサッカリンのような１種以上の甘味剤を含むことができる。
【００２６】
水の添加によって水性懸濁液の調製に適した分散性粉末もしくは顆粒は、分散剤もしくは湿潤剤、懸濁剤および１種以上の保存剤との混合物中に活性成分を提供する。好適な分散剤もしくは湿潤剤および懸濁剤は上で述べたものによって例示されている。追加の補助剤例えば甘味剤、矯味剤および着色剤も存在してよい。
【００２７】
化合物は非水性液状製剤の形、例えば活性成分を植物油例えばアラキス油、オリーブ油、ゴマ油もしくはピーナッツ油中に、または液状パラフィンのような鉱物油中に懸濁することにより製剤化することができる油性懸濁液でもよい。油性懸濁液は増粘剤例えば蜜ロウ、硬パラフィンまたはセチルアルコールを含むことができる。上で述べたような甘味剤および矯味剤を服用容易な経口製剤を提供するために添加することができる。これらの組成物はアスコルビン酸のような抗酸化剤の添加によって保存することができる。
【００２８】
本発明の化合物は当業者に既知の方法 (例えば、Ｃｈｉｅｎ；“Ｔｒａｎｓｄｅｒｍａｌ Ｃｏｎｔｒｏｌｌｅｄ Ｓｙｓｔｅｍｉｃ Ｍｅｄｉｃａｔｉｏｎｓ”；Ｍａｒｃｅｌ Ｄｅｋｋｅｒ，Ｉｎｃ，；１９８７．Ｌｉｐｐ ｅｔ ａｌ．ＷＯ９４／０４１５７，１９９４年３月３日を見よ。）を使用して経皮的に投与することもできる。例えば、任意に浸透促進剤を含有する適当な揮発性溶媒中の式Ｉ−VIの化合物の溶液もしくは懸濁液をマトリックス材料および殺バクテリア剤のような当業者に既知の追加の添加剤と組合わせることができる。滅菌後、生成した混合物は既知の操作に従って投与形に製剤化することができる。加えて、乳化剤および水との処理において、式Ｉ−VIの化合物の溶液もしくは懸濁液をローションもしくはザルベに処方することができる。
【００２９】
経皮デリバリシステムへ加工するために適した溶媒は当業者に既知であり、そしてエタノールもしくはプロピルアルコールのような低級アルコール、アセトンのような低級ケトン、酢酸エチルのような低級カルボン酸エステル、テトラヒドロフランのような極性エーテル、ヘキサン、シクロヘキサンもしくはベンゼンのような低級炭化水素、またはジクロロメタン、クロロホルム、トリクロロトリフロロエタンもしくはトリクロロフロロエタンのようなハロゲン化炭化水素を含む。好適な溶媒は低級アルコール、低級ケトン、低級カルボン酸エステル、極性エーテル、低級炭化水素およびハロゲン化炭化水素から選ばれた１種以上の材料の混合物を含むことができる。
【００３０】
経皮デリバリシステムのために適した浸透促進剤は当業者に既知であり、そして例えばエタノール、プロピレングリコールもしくはベンジルアルコールのようなモノヒドロキシまたはポリヒドロキシアルコール、ラウリルアルコールもしくはセチルアルコールのような飽和もしくは不飽和Ｃ8−Ｃ18脂肪アルコール、ステアリン酸のような飽和もしくは不飽和Ｃ8−Ｃ18脂肪酸、酢酸、カプロン酸、ラウリン酸、ミリスチン酸、ステアリン酸もしくはパルミチン酸、メチル、エチル、プロピル、イソプロピル、ｎ−ブチル、ｓｅｃ−ブチル、イソブチル、ｔ−ブチルもしくはモノグリセリンエステルのような２４までの炭素原子を有する飽和もしくは不飽和脂肪酸エステル、またはジイソプロピルアジペート、ジイソブチルアジペート、ジイソプロピルセバケート、ジイソプロピルマレエートまたはジイソプロピルフマレートのような２４までの炭素原子を有する飽和もしくは不飽和脂肪酸のジエステルを含む。追加の浸透促進剤はレシチンもしくはセファリンのようなフォスファチジル誘導体、テルペン、アミド、ケトン、尿素およびその誘導体、およびジメチルイソソルビッドおよびジエチレングリコールモノエチルエーテルのようなエーテルを含む。好適な浸透促進剤はモノヒドロキシもしくはポリヒドロキシアルコール、飽和もしくは不飽和Ｃ8−Ｃ18脂肪アルコール、飽和もしくは不飽和Ｃ8−Ｃ18脂肪酸、２４までの炭素原子を有する飽和もしくは不飽和脂肪酸エステル、合計２４までの炭素を有する飽和もしくは不飽和ジカルボン酸のジエステル、フォスファチジル誘導体、テルペン、アミド、ケトン、尿素およびその誘導体およびエーテルから選ばれた１種以上の材料の混合物を含むことができる。
【００３１】
経皮デリバリシステムのための好適な結合材料は当業者に既知であり、そしてポリアクリレート、シリコーン、ポリウレタン、ブロックコポリマー、スチレンブタジエンコポリマー、天然および合成ゴムを含む。セルロースエーテル、誘導体化ポリエチレンおよびシリケートもマトリックス成分として使用することができる。粘性樹脂もしくはオイルのような追加の添加剤をマトリックスの粘度を上げるために添加することができる。
【００３２】
本発明の薬剤組成物はＯ／Ｗエマルジョンの形でもよい。油相は例えばアラキス油もしくはオリーブ油のような植物油、または鉱油例えば液状パラフィン、またはこれらの混合物でよい。好適な乳化剤は天然ガム例えばアラビアガムもしくはトラガントガム、天然フォスファチジド例えば大豆レシチン、脂肪酸とヘキシトール無水物から誘導されたエステルもしくは部分エステル例えばソルビタンモノオレエート、および前記部分エステルとエチレンオキシドとの縮合物例えばポリオキシエチレンソルビタンモノオレエートであることができる。エマルジョンは甘味剤および矯味剤を含むことができる。
【００３３】
シロップおよびエリキサーは甘味剤例えばグリセロール、プロピレングリコール、ソルビトールもしくはショ糖と共に処方することができる。そのような処方は刺激緩和剤、保存剤、矯味剤および着色剤を含むことができる。
【００３４】
化合物は薬物投与のため経直腸もしくは経膣坐剤の形で投与することもできる。これら組成物は常温では固体であるが、しかし直腸内温度もしくは膣内温度では液体であり、そして薬物を放出するように直腸もしくは膣内で溶融する適当な非刺激性補助剤と薬物を混合することによって調製することができる。そのような材料はココアバターおよびポリエチレングリコールを含む。
【００３５】
さらに勃起不全の処置のためには、本薬剤組成物は陰核海綿体中への注射もしくは経尿道投与により、または尿道へ局所的に適用することによりペニスへ投与するのに適した任意の形を取ることができる。陰核海綿体への注射の場合、薬剤組成物は好適には食塩水溶液である。好ましくは薬剤組成物は経尿道投与に適した形であり、そしてこの場合組成物は典型的には溶液、軟膏もしくは坐剤の形である。典型的には薬剤組成物は性交開始前１ないし５０分、好ましくは１０ないし２０分前に投与される。
【００３６】
式Ｉの化合物のためのここに開示した使用のすべての療法において、毎日の経口投与療法は総体重ｋｇあたり好ましくは０．０１ないし２００ｍｇであろう。
【００３７】
静脈内、筋肉内、皮下および非経口注射を含む注射による、そして注入技術の使用による投与のための１日投与量は好ましくは総体重ｋｇあたり０．０１ないし２００ｍｇであろう。毎日の経膣療法は好ましくは総体重ｋｇあたり０．０１ないし２００ｍｇであろう。毎日の局所投与療法は好ましくは１日１ないし４回投与される総体重ｋｇあたり０．０１ないし２００ｍｇであろう。経皮濃度は好ましくは０．１ないし２００ｍｇ／ｋｇの１日投与量を維持するのに要する濃度であろう。毎日の吸入投与療法は好ましくは総体重ｋｇあたり０．０１ないし１０ｍｇであろう。
【００３８】
当業者には、特定の投与方法は治療薬を投与する時日常的に考慮される種々の要因に依存することが認められるであろう。しかしながら与えられた患者のための特定投与量レベルは、使用される特定化合物の活性、患者の年令、患者の体重、患者の一般的健康状態、患者の性、患者の食事、投与時間、投与ルート、排泄速度、薬物組合せ、および治療を受けている症状の重篤度を含む種々の要因に依存することも理解されるであろう。さらに当業者には、最適な処置コース、すなわち処置モードおよび限られた日数にわたって投与される式Ｉの化合物もしくは薬学的に許容されるその塩の１日あたりの投与回数は慣用の処置テストを使用して確かめることができることが認められるであろう。
【００３９】
本化合物および組成物はＲｈｏのキナーゼ阻害活性を示し、そのため上で挙げた適応症、例えばＲｈｏキナーゼによって仲介される適応症の処置に有用である。Ｒｈｏキナーゼによって仲介される適応症とは、その進行が少なくとも一部Ｒｈｏ経路を経由して進行する病気または疾状を意味する。
【００４０】
Ｒｈｏキナーゼ阻害活性、例えばＲＯＣＫ−１阻害は以下のように評価することができる。
【００４１】
ヒトＲＯＣＫのキナーゼドメインであるアミノ酸２７−５３０がＳｆ９こん虫細胞からグルタチオンＳ−トランフフェラーゼ融合タンパクとして単離される。このタンパクがグルタチオンセファロース４Ｂ（Ｐｈａｒｍａｃｉａ Ｂｉｏｔｅｃｈ，ＮＪ）アフィニティ精製により部分的に精製される。反応は５０ｍＭ Ｎ−（２−ヒドロキシエチル）ピペラジン−Ｎ’−（２−エタンスルホン酸）ｐＨ７．５、５μＭ ＭｇＣｌ2，１ｍＭジチオスレリトール、６μＭ ＡＴＰ, ０．２μＣｉ〔33Ｐ〕ＡＴＰ（ＮＥＮ，Ｂｏｓｔｏｎ，ＭＡ），１μｇミエリン塩基性タンパク、および０．１μｇ ＲＯＣＫ−１を含有する総体積１００μＬの９６ウエルプレート中で実施される。テスト化合物は１００％ジメチルスルホキシドに溶解され、適切な濃度に希釈され、そして反応へ添加される。ジメチルスルホキシドの最終濃度は０．５％をこえなかった。反応は室温で１時間行われる。反応はＨＣｌの７ｍＬの添加によって停止され、Ｐ３０メンブレン中へ移され、基質であるミエリン塩基性タンパクへ添加された〔33Ｐ〕ＡＴＰの量をカウント／分（ｃ．ｐ．ｍ．）としてＢｅｔｕＰｌａｔｅリーダー（Ｐａｃｋａｒｄ Ｉｎｓｔｒｕｍｅｎｔ Ｃｏ．，Ｍｅｒｉｃｌｅｎ，ＣＴ）中で読取られる。（すべての試薬は特記しない限りＳｉｇｍａ Ｃｈｅｍｉｃａｌ Ｃｏ．，Ｓｔ．Ｌｏｕｉｓ，ＭＯから購入した。）阻害％はテスト化合物の存在なしで添加された量と比較した時の、テスト化合物の存在下の放射活性の取込み量によって測定される。
【００４２】
また阻害活性は、Ｒｉｄｌｅｙ，Ａ．Ｊ．ａｎｄ Ａ．Ｈａｌｌ，Ｃｅｌｌ ７０：３８９−３９９（１９９２）に記載されたのと本質的に同じように実施されるストレス線維生成の測定によって評価することができる。ヒト線維肉腫ＨＴ１０８０（ＣＣＬ−１２１，Ａｍｅｒｉｃａｎ Ｔｙｐｅ Ｃｕｌｔｕｒｅ Ｃｏｌｌｅｃｔｉｏｎ，Ｍａｎａｓｓａ，ＶＡ）細胞が１０％ウシ胎児血清を補強したＤｅｌｂｅｃｏ修正イーグル培地（ＤＭＥＭ，Ｇｉｂｃｏ）中の２．５×１０4細胞／ウエルにおいて６ウエル組織培養プレート（Ｃｏｓｔａｒ）中の２２×２２ｍｍ＃ガラスカバースリップ上にプレートされる。細胞は加湿された５％ＣＯ2雰囲気中に維持される。２４時間後培養倍地を除去し、１０％ウシ胎児血清なしの培地で交換され、細胞は追加の４８時間培養される。テスト化合物は１００％ジメチルスルホキシドに溶解され、適当な濃度に希釈され、ストレス線維の生成誘発前６０分に培地へ添加される。ジメチルスルホキシドの最終濃度は０．２５％をこえなかった。ストレス線維生成はリソフォスファチジン酸（１−オレイル−２−ヒドロキシ−Ｓｎ−グリセロール−３−フォスフェート，Ａｖａｎｔｉ Ｐｏｌａｒ−Ｌｉｐｉｄｓ，Ａｌｂａｓｔｅｒ，ＡＩ）を３７℃において１５分間０．１％脂肪酸不含ウシ血清アルブミンを含んでいるＤｅｌｂｅｃｏ修正イーグル培地へ１０μＭ最終濃度に添加することによって誘発される。細胞はリン酸塩緩衝食塩水（ＰＢＳ）中４％パラホルムアルデヒド（Ｐｏｌｙ Ｓｃｉｅｎｔｉｆｉｃ，Ｂａｙ Ｓｈｏｒｅ，ＮＪ）で１５分間固定される。細胞は次にＰＢＳ中３回洗浄され、そして次に４０ｍＭピペラジン−Ｎ，Ｎ’−ビス（２−エタンスルホン酸）、５０ｍＭ（２−ヒドロキシエチル）ピペラジン−Ｎ’−（２−エタンスルホン酸）、０．１％トリトンＸ−１００、７５ｍＭ ＮａＣｌ，ｍＭ ＭｇＣｌ2, ０．５ｍＭ ＥＤＴＡ，ｐＨ７．２を含んでいる溶液を用いて室温で２分間浸透性化される。細胞は各回ＰＢＳ中５分間３回洗浄され、そして次にアクチンストレス線維がＰＢＳ中１０単位／ｍＬのローダミンファロイジン（Ｍｏｌｅｃｕｌａｒ Ｐｒｏｂｅｓ，Ｅｕｇｅｍｅ，ＯＲ）を用いて室温で６０分間染色される。細胞はＰＢＳで３回洗浄され、カバースリップがガラス顕微鏡スライド上に載置される。各スライド上のストレス線維陽性細胞のパーセントがニコンＬａｂｐｈｔｏ−２顕微鏡を用いて肉眼で決定された。少なくともプレートあたり１００細胞がカウントされ、そして実験は２回実施された。阻害パーセントは、テスト化合物が存在しない場合のストレス線維陽性細胞の数と比較した時、テスト化合物存在下におけるストレス線維陽性線維の数をカウントすることによって測定される。
【００４３】
上のプロトコールを用いて、ここに開示した化合物のすべてはＲｈｏキナーゼ阻害活性を有することが決定される。
【００４４】
本発明の化合物は、ルーチンな慣用化学的方法に従って、および／または以下に記載するように、商業的に入手できるか、またはルーチンな慣用化学的方法に従って製造することができる出発物質から製造することができる。化合物の製造のための一般的方法が以下に与えられ、そして代表的化合物の製造が実施例に特定的に例証されている。
【００４５】
略号
ここで以下の略号が使用される時、それらは以下の意味を持つ。
Figure 2004528314
Figure 2004528314
【００４６】
一般的製造方法
以下の一般的方法を記載するために使用した式中で、Ｒ1およひＲ2は水素もしくはメトキシであり、Ｒ3はメトキシエチル、シクロプロピル、４−フロロフェニルもしくは４−ピリジルであり、本発明の化合物Ｉ−VIを製造するために適宜選択される。
【００４７】
一般法Ａ：
【００４８】
【化２１】
Figure 2004528314
【００４９】
ＴＨＦ／水中の化合物１および、そして酢酸カリウムの混合物を室温で一夜攪拌する。混合物へ水を加え、沈澱を生成させる。この沈澱を水で洗い、濾過し、そして高真空下乾燥して化合物３を得る。
【００５０】
一般法Ｂ：
【００５１】
【化２２】
Figure 2004528314
【００５２】
化合物３と、置換アミンもしくはアニリンの混合物を１４０℃へ２時間加熱する。混合物を室温へ冷却し、そしてエーテルで処理して沈澱を生成させるか、またはシリカゲルクロマトグラフィーによって精製する。沈澱の精製：沈澱を濾過し、エーテルで数回洗い、そして高真空下乾燥して生成物を得る。
【００５３】
さらに考究することなく、当業者は以上の説明を利用して本発明をその全範囲において利用することができると信じられる。それ故以下の好ましい特定の具体例は単に例証であり、如何なる態様においても開示の残部の限定ではないと考えるべきである。
【００５４】
以上および以下の実施例において、すべての温度は未補正の摂氏で与えられ、そして特記しない限りすべての部およびパーセントは重量による。
【００５５】
２００１年３月２３日に出願された米国仮特許出願Ｎｏ．６０／２７７，９７４および２００１年８月２９日に出願された米国仮特許出願Ｎｏ．６０／３１５，３３８を含む、以前および以下に引用したすべての出願、特許および発表の全体の開示が参照としてここに取入れられる。
【００５６】
〔実施例１〕
２−Ｎ−５’−アミノインダゾール−４−クロロ−６，７−ジメトキシキナゾリン
【００５７】
【化２３】
Figure 2004528314
【００５８】
ＴＨＦ／水（２Ｌ／０．９Ｌ）中の２，４−ジクロロ−６，７−ジメトキシキナゾリン（Ａｌｄｒｉｃｈ Ｃｈｅｍｉｃａｌ Ｃｏ．，２２６ｇ，０．８７４ｍｏｌ）、５−アミノインダゾール（１３０ｇ，０．９８ｍｏｌ）および酢酸カリウム（１１１．５ｇ，１．１４ｍｏ．）の混合物を室温で一夜攪拌する。水（２Ｌ）を混合物へ加え、沈澱を生成させる。この沈澱を水で洗い、濾過し、高真空下で乾燥し、生成物を灰色粉末として得る。
【００５９】
〔実施例２〕
Ｎ−〔２−（２，４−ジクロロフェニル）−４−キナゾリニル〕−Ｎ−（１Ｈ−インダゾール−５−イル）アミンの製造
【００６０】
【化２４】
Figure 2004528314
【００６１】
ブタノール（５０ｍＬ）中の４−クロロ−２−フェニルキナゾリン（Ａｌｄｒｉｃｈ Ｃｈｅｍｉｃａｌ Ｃｏ．，７．２ｇ，３０ｍｏｌ）と、５−アミノインダゾール（３．９９ｇ，３０ｍｍｏｌ）の混合物を１００℃へ一夜加熱する。溶媒を減圧除去した後、粗生成物をシリカゲルクロマトグラフィー（酢酸エチル／ヘキサン２０％ないし８０％勾配）よって精製し、実施例２の化合物（３．６ｇ）を得る。ＨＰＬＣ／ＭＳ：（Ｍ＋Ｈ）+３３８ｍ／ｚ，保持時間（ＨＰＬＣ／ＭＳ）＝３．６５分
【００６２】
実施例３−６への一般的合成ルート
【００６３】
【化２５】
Figure 2004528314
【００６４】
〔実施例３〕
Ｎ２−（４−フロロフェニル）−Ｎ４−（１Ｈ−インダゾール−５−イル）−６，７−ジメトキシ−２，４−キナゾリンジアミン
【００６５】
【化２６】
Figure 2004528314
【００６６】
ｎ−ブタノール（１ｍＬ）中の２−フロロ−Ｎ−（１Ｈ−インダゾール−５−イル）−６，７−ジメトキシ−４−キナゾリンアミン（０．１ｍｍｏｌ）と、４−フロロアニリン（０．３ｍｍｏｌ）の懸濁液を９０℃で７２時間振とうする。溶媒を蒸発し、残渣をＨＰＬＣによって精製し、純粋な生成物を得る。（Ｍ＋Ｈ）+＝４３１，ＲＴ（ＬＣ−ＭＳ）＝２．９２
【００６７】
実施例３のための上に記載した方法を使用し、そして適切な出発物質に置換し、実施例４−６の化合物を同様に製造し、下の表１に要約する。
【００６８】
【化２７】
Figure 2004528314
【００６９】
【表１】
Figure 2004528314
【００７０】
上の実施例は本発明の一般的にまたは特定的に記載した反応剤および／または作業条件を以上の実施例に使用したそれらに置換することにより、類似の成功度をもってくり返すことができる。【Technical field】
[0001]
This application is a provisional application filed on March 23, 2001. No. 60 / 277,974 and U.S. patent application no. Claim the benefit of the filing date of 60 / 315,338.
[0002]
The present invention relates to compounds, derivatives thereof, their synthesis, and their use as Rho kinase inhibitors. These compounds of the invention are useful for tumor growth arrest, treatment of erectile dysfunction, and other indications mediated by Rho kinase, such as coronary heart disease.
[Background]
[0003]
A number of human and animal disease pathologies, including hypertension, erectile dysfunction, coronary circulatory disturbances, neurodegeneration disorders and cancer, can be directly linked to changes in the actin cytoskeleton. These diseases provide a serious unmet medical need. The actin cytoskeleton is composed of a network of actin filaments and actin-binding proteins found in all eukaryotic cells. In smooth muscle cells, actin cytoskeletal assembly and dissemination is the primary driving force responsible for smooth muscle contraction and relaxation. In non-smooth muscle cells, dynamic relocation of the actin cytoskeleton is specialized such as cell morphology, cell mobility, actin stress fiber formation, cell adhesion, and axonal contraction, phagocytosis or cell division Responsible for the regulation of cell function (Van Aelst, et al. Genes Dev 1997, 11, 295).
[0004]
The actin cytoskeleton is controlled by a family of proteins that are a subset of the Ras superfamily. This subset currently consists of RhoA to G and RhoG (collectively referred to as Rho), Rac1 and 2, Cdc42Hs and G25K and TC10 isoforms (Mackay, et al. J Bio Chem 1998, 273, 20685). These three proteins are GTP (guanine nucleotide triphosphate) binding proteins with intrinsic GTPase activity. They act as molecular switches and cycle between bound GDP (guanine nucleotide diphosphate) and the active GTP binding state. Using biochemical and genetic engineering, it became possible to assign functions to each family member. When activated, the Rho protein controls the formation of thick bundles of actin stress fibers and actin filaments and integrin clustering in the focal adhesion complex. When activated, the Rac protein controls the production of membrane undulations on the cell surface, and Cdc42 controls the production of filamentous feet. Together, these protein families play an important role in the control of key cell functions, including cell motility, axon guidance, cell division, and changes in cell morphology, shape and polarity.
[0005]
Depending on the type of cell and the activated receptor, Rho proteins can regulate various biological responses. In smooth muscle cells, Rho protein is responsible for calcium sensitization during smooth muscle contraction. In non-smooth muscle cells, Rho GTPase is lysophosphatidic acid (LPA), thrombin and thromboxane A.2Responsible for cellular responses to agonists such as (Fukuda, et al. Trends Polar Sci 2001, 22, 32). Agonist responses are linked through heterotrimeric G protein, Galpha12 or Galpha13, although other receptors may also be involved (Goetzl, et al. Cancer Res 1999, 59, 4732; Buhl, et al. J Biol Chem 1995, 270, 24681). When activated, Rho GTPase activates a number of downstream factors including PIP5-kinase, lowsekin, lophyrin, PKN, and Rho kinase isoforms ROCK-1 / ROK beta and ROCK-1 / ROK alpha (Mackay et al. J Biol Chem 1998, 273, 20687; Aspenstrom, Curr Opin Cell Biol 1999, 11, 95; Amano, et al. Exp Cell Res 2000, 261, 44).
[0006]
Rho kinase has been identified as a RhoA interacting protein isolated from bovine brain (Matsui, et al. Embo J 1996, 15, 2208). It is a member of the muscular dystrophy family of protein kinases and contains a serine / threonine domain at the amino terminus, a coiled domain at the central region, and a Rho interaction domain at the carboxy terminus (Amano, et al. Exp Cell Res). 2000, 261, 44). Its kinase activity is enhanced when bound to GTP-bound RhoA, and it reproduces the multiple activities of activated RhoA when introduced into cells. In smooth muscle cells, Rho kinase mediates calcium sensitization and smooth muscle contraction, and inhibition of Rho kinase blocks 5-HT and phenylephrine agonists induced by muscle contraction. When introduced into non-smooth muscle cells, Rho kinase induces stress fibrogenesis and is required for RhoA-mediated cell transformation (Sahai, et al. Curr Biol 1999, 9, 136). Rho kinase can be obtained by phosphorylation through myosin light chain (Somlyo, et al. J Physio (Lond) 2000, 522 pt2, 177), myosin light chain phosphatase binding subunit (Fukata, et al. J Cell Biol 1998, 141, 409) and a number of downstream proteins including LIM-kinase 2 (Sumi, et al. J BioChem 2001, 276, 670).
[0007]
Inhibition of Rho kinase in animal models has demonstrated numerous benefits of Rho kinase inhibitors for human disease. (+)-Trans-4- (1-aminoethyl)-(pyridin-4-ylaminocarbonyl) cyclohexanedihydrochloride-hydrate (WO00 / 078351, WO00 / 057913) and substituted isoquinolinesulfonyl compounds (EP00187371) There are several patents claiming as Rho kinase inhibitors having activity in animal models. These include hypertension (Vehata, et al. Nature 1997, 389, 990), arteriosclerosis (Retzer, et al. FEBS Lett 2000, 466, 70), restenosis (Eto, et al. Am J Physiol Heart Circ Physiol 2000, Negoro, et al., Biochem Biophys Res Commun 1999, 261, 211), cerebral ischemia (Uehata et al. Nature 1997, 389, 990); Seaholtz, et al. Circ Res 1999, 84, 1186; Hitomi, et al. Life Sci 2000, 67, 1929; Yamamoto, et al. J Cardiovas Pharmacol 2000, 35, 203), cerebral vasospasm (Sato, et al. Circ Res 2000, 87, 195; Kim, et al. Neurosurgery 2000, 46, 440), erectile dysfunction (Chitaley, et al. Nat. Med 2001, 7, 119), central nervous system disorders such as neurodegeneration and spinal cord disorders (Hara, et al. J Neurosurg 2000, 93, 94; Toshima, et al. Stroke 2000, 31, 245), Rho kinase. Neoplasia has been shown to inhibit tumor cell growth and metastasis (Itoh, et al. Nat Med 1999, 5, 221; Somlye, et al. Biochem Biophys Re Commun 2000, 269, 652), angiogenesis (Uchida, et al. Biochem Biophys Res Commun 2000, 269, 633; Gingras, et al. Biochem J 2000, 348 Pt 2,273), platelet aggregation (Klages, et al. J Cell Biol 1999, 144, 745; Retzer, et al. Cell Signal 2000, 12, 645) and leukocyte aggregation (Kawaguchi, et al. Eur J Pharmacol 2000, 403, 203; Sanchez-Madrid, et al. Embo J. 1999, 18, 501), arterial hemostasis disorder, asthma (Setoguchi, et al. Br J Pharmacol 20 Nakahara, et al. Eur J Pharmacol 2000, 389, 103), intraocular pressure regulation (Honjo, et al. Invest Ophthalmol Vis Sci 2001, 42, 137), and bone resorption (Chellaiah, et al. J Biol Chem 2000, 275, 11993; Zhang, et al. J Cell Sci 1995, 108, 2285).
[0008]
In patients, inhibition of Rho kinase has the benefit of controlling cerebral vasospasm and ischemia after subarachnoid hemorrhage (Pharmacia Japan 1995, 1470, 16).
DISCLOSURE OF THE INVENTION
[0009]
The compounds provided in the present invention and their derivatives are useful as Rho kinase inhibitors, so that hypertension, arteriosclerosis, restenosis, cerebral ischemia, cerebral vasospasm, nerve degeneration, bone marrow injury, breast, prostate, It has utility in the treatment of colorectal, ovarian, brain and lung cancers and their metastases, hemostatic disorders, asthma, glaucoma and osteoporosis.
[0010]
In addition, the compounds of the present invention are useful for treating erectile dysfunction, ie erectile dysfunction mediated by Rho kinase. Erectile dysfunction can be defined as the inability to obtain or maintain an erection appropriate for intercourse. WO 94/28902, U.S. Pat. S. P. 6,103,765 and U.S. Pat. S. P. See 6,124,461.
[0011]
The present invention provides compounds of the following formula:
[0012]
Embedded image
Figure 2004528314
[0013]
Embedded image
Figure 2004528314
[0014]
Embedded image
Figure 2004528314
[0015]
Embedded image
Figure 2004528314
[0016]
Embedded image
Figure 2004528314
[0017]
Embedded image
Figure 2004528314
[0018]
The present invention is also directed to pharmaceutically acceptable salts of formula I-VI. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and are hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfonic, acetic, trifluoroacetic, malic, tartaric acid Salts of inorganic and organic acids such as citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include alkali cations (eg Li+, Na+Or K+), Alkaline earth cations (eg Mg++, Ca++, Or Ba++), Salts of inorganic bases such as salts containing ammonium cations, and triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4 -Diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] nonene-5 (DBN) and 1,8-diazabicyclo [5.4.0] undecene-7 (BBU) Organic base acid salts containing aliphatic and aromatic substituted ammonium and quaternary ammonium cations such as those generated from protonation or peralkylation of
[0019]
Many of the compounds of formula I-VI have asymmetric carbon atoms and therefore exist in racemic and optically active forms. Methods for separating enantiomeric and diastereomeric mixtures are well known to those skilled in the art. The invention includes any isolated racemic or optically active form of a compound of formula I-VI having Rho kinase inhibitory activity.
[0020]
The present invention also includes a pharmaceutical composition comprising a compound of formula I-VI and a physiologically acceptable carrier.
[0021]
The invention further comprises treating a Rho-kinase mediated indication by administering a compound of formula I-VI, or a pharmaceutical composition comprising a compound of formula I-VI. Thus, the present invention is directed against hypertension, arteriosclerosis, restenosis, cardiovascular diseases such as cerebral ischemia or spasticity, central nervous system disorders such as nerve degeneration and spinal cord injury, erectile dysfunction such as PDE-5. Treating patients who do not have a satisfactory response and cancers mediated by Rho kinase (eg tumor growth) by administering an effective amount of a compound of formula I, for example, to a host in need thereof. Including. Cancers and tumors mediated by Rho kinase include breast, large intestine, prostate, ovary, brain and lung cancers and their metastases.
[0022]
The compounds can be administered orally, topically, parenterally, by inhalation or spray, vaginally, enterally or sublingually in dosage unit formulations. Administration by injection includes intravenous, intraarterial, intramuscular, subcutaneous and parenteral injection and the use of infusion techniques. Dermal administration can include topical or transdermal administration. One or more compounds may be present with one or more non-toxic pharmaceutically acceptable carriers and, if desired, other active ingredients.
[0023]
Compositions intended for oral use can be prepared according to any suitable known method for the manufacture of pharmaceutical compositions. Such compositions can contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, colorants and preservatives to provide a dosage form that can be taken. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable adjuvants which are suitable for the manufacture of tablets. These adjuvants include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, and binders such as magnesium stearate, stearin Acid or talc. Tablets can be uncoated or delayed disintegration and absorption in the gastrointestinal tract, thereby allowing them to be coated for extended periods of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. These compounds can also be prepared in a solid immediate release form.
[0024]
Formulations for oral use can also be provided as hard gelatin capsules, in which case the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water or an oil medium For example, soft gelatin capsules mixed with peanut oil, liquid paraffin or olive oil.
[0025]
Aqueous suspensions containing the active ingredients in admixture with adjuvants suitable for the manufacture of aqueous suspensions can also be used. Such adjuvants are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents are natural phosphatides such as lecithin or alkylene oxides of fatty acids Condensates such as polyoxyethylene stearate, or alkylene oxide condensates with long chain fatty alcohols such as heptadecaethyleneoxycetanol, or alkylenes of partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate Oxide condensates or alkylene oxide condensates of partial esters derived from fatty acids and hexitol anhydrides such as poly It can be a carboxymethyl sorbitan monooleate. Aqueous suspensions or one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl ester, one or more colorants, one or more flavoring agents, and one such as sucrose or saccharin The above sweeteners can be included.
[0026]
Dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional adjuvants such as sweetening, flavoring and coloring agents may also be present.
[0027]
The compounds can be formulated in a non-aqueous liquid formulation, for example by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. It may be a turbid liquid. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents such as those described above can be added to provide an easy to take oral formulation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0028]
The compounds of the present invention may be prepared by methods known to those skilled in the art (see, for example, Chien; “Transdermal Controlled Systems Medicines”; Marcel Dekker, Inc .; 1987. Lipp et al. WO 94/04157, March 3, 1994). It can also be administered transdermally. For example, a solution or suspension of a compound of formula I-VI in a suitable volatile solvent optionally containing a penetration enhancer is combined with additional additives known to those skilled in the art such as matrix materials and bactericides. Can be matched. After sterilization, the resulting mixture can be formulated into dosage forms according to known procedures. In addition, in treatment with emulsifiers and water, solutions or suspensions of compounds of formula I-VI can be formulated into lotions or salves.
[0029]
Suitable solvents for processing into transdermal delivery systems are known to those skilled in the art and include lower alcohols such as ethanol or propyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, tetrahydrofuran. Polar ethers such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane or trichlorofluoroethane. Suitable solvents can include a mixture of one or more materials selected from lower alcohols, lower ketones, lower carboxylic esters, polar ethers, lower hydrocarbons and halogenated hydrocarbons.
[0030]
Penetration enhancers suitable for transdermal delivery systems are known to those skilled in the art and are saturated or unsaturated such as monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, lauryl alcohol or cetyl alcohol. Saturation C8-C18Saturated or unsaturated C such as fatty alcohol, stearic acid8-C18Up to 24 such as fatty acid, acetic acid, caproic acid, lauric acid, myristic acid, stearic acid or palmitic acid, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl or monoglycerin ester Saturated or unsaturated fatty acid esters having carbon atoms, or diesters of saturated or unsaturated fatty acids having up to 24 carbon atoms such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate or diisopropyl fumarate. Additional penetration enhancers include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, urea and derivatives thereof, and ethers such as dimethyl isosorbide and diethylene glycol monoethyl ether. Suitable penetration enhancers are monohydroxy or polyhydroxy alcohols, saturated or unsaturated C8-C18Fatty alcohol, saturated or unsaturated C8-C18From fatty acids, saturated or unsaturated fatty acid esters having up to 24 carbon atoms, diesters of saturated or unsaturated dicarboxylic acids having up to 24 carbons in total, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives and ethers It may contain a mixture of one or more selected materials.
[0031]
Suitable bonding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block copolymers, styrene butadiene copolymers, natural and synthetic rubbers. Cellulose ethers, derivatized polyethylene and silicates can also be used as matrix components. Additional additives such as viscous resins or oils can be added to increase the viscosity of the matrix.
[0032]
The pharmaceutical composition of the present invention may be in the form of an O / W emulsion. The oily phase may be a vegetable oil, for example arachis oil or olive oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifiers are natural gums such as gum arabic or tragacanth, natural phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensates of said partial esters with ethylene oxide such as polyoxy It can be ethylene sorbitan monooleate. The emulsion can contain sweetening and flavoring agents.
[0033]
Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations can contain irritating agents, preservatives, flavoring and coloring agents.
[0034]
The compounds can also be administered in the form of rectal or vaginal suppositories for drug administration. These compositions are solid at room temperature, but are liquid at rectal or vaginal temperatures and are mixed with a suitable nonirritating adjuvant that melts in the rectum or vagina to release the drug. Can be prepared. Such materials include cocoa butter and polyethylene glycol.
[0035]
Furthermore, for the treatment of erectile dysfunction, the pharmaceutical composition may be in any form suitable for administration to the penis by injection into the clitoral corpus cavernosum or transurethral administration or by topical application to the urethra. Can take. For injections into the clitoral corpus cavernosum, the pharmaceutical composition is preferably a saline solution. Preferably the pharmaceutical composition is in a form suitable for transurethral administration, and in this case the composition is typically in the form of a solution, ointment or suppository. Typically, the pharmaceutical composition is administered 1 to 50 minutes, preferably 10 to 20 minutes before the start of sexual intercourse.
[0036]
In all therapies of use disclosed herein for compounds of formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg / kg of total body weight.
[0037]
The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injection, and by use of infusion techniques will preferably be from 0.01 to 200 mg per kg body weight. Daily vaginal therapy will preferably be from 0.01 to 200 mg / kg of total body weight. Daily topical therapy will preferably be from 0.01 to 200 mg / kg of total body weight administered 1 to 4 times per day. The transdermal concentration will preferably be that required to maintain a daily dosage of 0.1 to 200 mg / kg. Daily inhalation therapy will preferably be from 0.01 to 10 mg / kg of total body weight.
[0038]
One skilled in the art will recognize that the particular mode of administration will depend on various factors that are routinely considered when administering a therapeutic agent. However, the specific dose level for a given patient depends on the activity of the specific compound used, patient age, patient weight, patient general health, patient sex, patient diet, administration time, administration It will also be appreciated that it will depend on a variety of factors including route, excretion rate, drug combination, and the severity of the condition being treated. In addition, those skilled in the art will use conventional treatment tests to determine the optimal course of treatment, ie the mode of treatment and the number of daily doses of the compound of formula I or pharmaceutically acceptable salt administered over a limited number of days. It will be appreciated that this can be verified.
[0039]
The compounds and compositions exhibit Rho kinase inhibitory activity and are therefore useful in the treatment of the indications listed above, eg, indications mediated by Rho kinase. An indication mediated by Rho kinase means a disease or condition whose progression proceeds at least in part via the Rho pathway.
[0040]
Rho kinase inhibitory activity, such as ROCK-1 inhibition, can be evaluated as follows.
[0041]
Amino acids 27-530, the kinase domain of human ROCK, are isolated from Sf9 insect cells as a glutathione S-transferase enzyme fusion protein. This protein is partially purified by glutathione sepharose 4B (Pharmacia Biotech, NJ) affinity purification. The reaction was 50 mM N- (2-hydroxyethyl) piperazine-N ′-(2-ethanesulfonic acid) pH 7.5, 5 μM MgCl2, 1 mM dithiothreitol, 6 μM ATP, 0.2 μCi [33Performed in 96 well plates with a total volume of 100 μL containing P] ATP (NEN, Boston, Mass.), 1 μg myelin basic protein, and 0.1 μg ROCK-1. The test compound is dissolved in 100% dimethyl sulfoxide, diluted to the appropriate concentration and added to the reaction. The final concentration of dimethyl sulfoxide did not exceed 0.5%. The reaction is carried out at room temperature for 1 hour. The reaction was stopped by the addition of 7 mL of HCl, transferred into a P30 membrane and added to the substrate myelin basic protein [33The amount of P] ATP is read in a BetaPlate reader (Packard Instrument Co., Mericlen, CT) as counts per minute (cpm). (All reagents were purchased from Sigma Chemical Co., St. Louis, MO unless otherwise specified.) Percent inhibition is the radioactivity in the presence of test compound as compared to the amount added without the presence of test compound. Measured by the amount of uptake.
[0042]
Inhibitory activity is also shown in Ridley, A. et al. J. et al. and A. Hall, Cell 70: 389-399 (1992) and can be assessed by measurement of stress fiber production performed essentially as described. Human fibrosarcoma HT1080 (CCL-121, American Type Culture Collection, Manassa, Va.) 2.5 × 10 × in Delbeco's modified Eagle medium (DMEM, Gibco) supplemented with 10% fetal bovine serum.FourCells are plated onto 22 × 22 mm # glass coverslips in 6 well tissue culture plates (Costar) in cells / well. Cells are humidified 5% CO2Maintained in atmosphere. After 24 hours, the culture medium is removed and replaced with medium without 10% fetal calf serum and the cells are cultured for an additional 48 hours. The test compound is dissolved in 100% dimethyl sulfoxide, diluted to an appropriate concentration, and added to the medium 60 minutes before induction of stress fiber formation. The final concentration of dimethyl sulfoxide did not exceed 0.25%. Stress fiber formation was achieved by lysophosphatidic acid (1-oleyl-2-hydroxy-Sn-glycerol-3-phosphate, Avanti Polar-Lipids, Albaster, AI) at 37 ° C. for 15 minutes with 0.1% fatty acid-free cattle. Induced by adding 10 μM final concentration to Delbeco modified Eagle medium containing serum albumin. Cells are fixed with 4% paraformaldehyde (Poly Scientific, Bay Shore, NJ) in phosphate buffered saline (PBS) for 15 minutes. The cells are then washed 3 times in PBS and then 40 mM piperazine-N, N′-bis (2-ethanesulfonic acid), 50 mM (2-hydroxyethyl) piperazine-N ′-(2-ethanesulfonic acid). 0.1% Triton X-100, 75 mM NaCl, mM MgCl2, And is permeabilized for 2 minutes at room temperature using a solution containing 0.5 mM EDTA, pH 7.2. Cells are washed 3 times for 5 minutes each in PBS and then actin stress fibers are stained with 10 units / mL rhodamine phalloidin (Molecular Probes, Eugene, OR) in PBS for 60 minutes at room temperature. Cells are washed 3 times with PBS and a coverslip is placed on a glass microscope slide. The percentage of stress fiber positive cells on each slide was determined visually using a Nikon Labphto-2 microscope. At least 100 cells per plate were counted and the experiment was performed twice. The percent inhibition is measured by counting the number of stress fiber positive fibers in the presence of the test compound when compared to the number of stress fiber positive cells in the absence of the test compound.
[0043]
Using the above protocol, all of the compounds disclosed herein are determined to have Rho kinase inhibitory activity.
[0044]
The compounds of the present invention are prepared according to routine conventional chemical methods and / or from starting materials that are commercially available or can be prepared according to routine conventional chemical methods, as described below. Can do. General methods for the preparation of compounds are given below and the preparation of representative compounds is specifically illustrated in the examples.
[0045]
Abbreviation
Here, when the following abbreviations are used, they have the following meanings.
Figure 2004528314
Figure 2004528314
[0046]
General manufacturing method
In the formula used to describe the following general method:1R2Is hydrogen or methoxy and RThreeIs methoxyethyl, cyclopropyl, 4-fluorophenyl or 4-pyridyl, and is appropriately selected for producing the compounds I-VI of the present invention.
[0047]
General method A:
[0048]
Embedded image
Figure 2004528314
[0049]
A mixture of Compound 1 in THF / water and potassium acetate is stirred overnight at room temperature. Water is added to the mixture to form a precipitate. The precipitate is washed with water, filtered and dried under high vacuum to give compound 3.
[0050]
General method B:
[0051]
Embedded image
Figure 2004528314
[0052]
A mixture of compound 3 and a substituted amine or aniline is heated to 140 ° C. for 2 hours. The mixture is cooled to room temperature and treated with ether to form a precipitate or purified by silica gel chromatography. Purification of the precipitate: The precipitate is filtered, washed several times with ether and dried under high vacuum to give the product.
[0053]
Without further consideration, it is believed that one skilled in the art, using the above description, can utilize the present invention in its full scope. The following preferred specific embodiments are therefore to be considered merely illustrative and not limiting of the remainder of the disclosure in any way.
[0054]
In the examples above and below, all temperatures are given in uncorrected degrees Celsius, and all parts and percentages are by weight unless otherwise specified.
[0055]
US provisional patent application no. 60 / 277,974 and US provisional patent application no. The entire disclosures of all applications, patents and publications cited above and below, including 60 / 315,338, are hereby incorporated by reference.
[0056]
[Example 1]
2-N-5'-aminoindazole-4-chloro-6,7-dimethoxyquinazoline
[0057]
Embedded image
Figure 2004528314
[0058]
2,4-Dichloro-6,7-dimethoxyquinazoline (Aldrich Chemical Co., 226 g, 0.874 mol), 5-aminoindazole (130 g, 0.98 mol) and acetic acid in THF / water (2 L / 0.9 L) A mixture of potassium (111.5 g, 1.14 mo.) Is stirred overnight at room temperature. Water (2 L) is added to the mixture and a precipitate is formed. The precipitate is washed with water, filtered and dried under high vacuum to give the product as a gray powder.
[0059]
[Example 2]
Preparation of N- [2- (2,4-dichlorophenyl) -4-quinazolinyl] -N- (1H-indazol-5-yl) amine
[0060]
Embedded image
Figure 2004528314
[0061]
A mixture of 4-chloro-2-phenylquinazoline (Aldrich Chemical Co., 7.2 g, 30 mol) and 5-aminoindazole (3.99 g, 30 mmol) in butanol (50 mL) is heated to 100 ° C. overnight. After removing the solvent under reduced pressure, the crude product is purified by silica gel chromatography (ethyl acetate / hexane 20% to 80% gradient) to give the compound of Example 2 (3.6 g). HPLC / MS: (M + H)+338 m / z, retention time (HPLC / MS) = 3.65 minutes
[0062]
General synthetic route to Examples 3-6
[0063]
Embedded image
Figure 2004528314
[0064]
Example 3
N2- (4-Fluorophenyl) -N4- (1H-indazol-5-yl) -6,7-dimethoxy-2,4-quinazolinediamine
[0065]
Embedded image
Figure 2004528314
[0066]
2-Fluoro-N- (1H-indazol-5-yl) -6,7-dimethoxy-4-quinazolinamine (0.1 mmol) and 4-fluoroaniline (0.3 mmol) in n-butanol (1 mL) The suspension is shaken at 90 ° C. for 72 hours. The solvent is evaporated and the residue is purified by HPLC to give the pure product. (M + H)+= 431, RT (LC-MS) = 2.92
[0067]
Using the method described above for Example 3 and substituting the appropriate starting materials, the compounds of Examples 4-6 are prepared analogously and summarized in Table 1 below.
[0068]
Embedded image
Figure 2004528314
[0069]
[Table 1]
Figure 2004528314
[0070]
The above examples can be repeated with similar success by substituting the generally and specifically described reactants and / or operating conditions of the present invention for those used in the previous examples.

Claims (12)

下記式ＩないしVIのいずれかの化合物または薬剤的に許容し得るそれらの塩：
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
 A compound of any of the following formulas I to VI or a pharmaceutically acceptable salt thereof:
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
Figure 2004528314
 式Ｉの請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula I:
Figure 2004528314
 式IIの請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula II:
Figure 2004528314
 式III の請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula III:
Figure 2004528314
 式IVの請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula IV:
Figure 2004528314
 式Ｖの請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula V:
Figure 2004528314
 式VIの請求項１の化合物：
Figure 2004528314
 The compound of claim 1 of formula VI:
Figure 2004528314
 請求項１の化合物をそれを必要とする宿主へ投与することよりなる、Ｒｈｏキナーゼによって仲介される適応症を処置する方法。A method of treating an indication mediated by Rho kinase, comprising administering the compound of claim 1 to a host in need thereof. 請求項１の化合物をそれを必要とする宿主へ投与することよりなる、高血圧、動脈硬化、再狭窄、脳虚血症、脳血管痙れん、神経退化、骨髄傷害、乳房、大腸、前立腺、卵巣、脳もしくは肺のがん、止血障害、喘息、緑内障、骨粗しょう症、または勃起不全を処置する方法。2. Hypertension, arteriosclerosis, restenosis, cerebral ischemia, cerebrovascular spasm, nerve degeneration, bone marrow injury, breast, large intestine, prostate, ovary comprising administering the compound of claim 1 to a host in need thereof To treat cancer of the brain, lung, hemostasis, asthma, glaucoma, osteoporosis, or erectile dysfunction. 宿主はヒトである請求項８の方法。The method of claim 8, wherein the host is a human. 宿主はヒトである請求項９の方法。The method of claim 9, wherein the host is a human. （ａ）塩基の存在下式１の化合物を式２の化合物を反応させて式３の化合物を製造し、
Figure 2004528314
（ｂ）場合により式３の化合物をＲ3ＮＨ2またはＡｒ2ＮＨ2と反応させて式４の化合物を製造する
Figure 2004528314
（式中Ｒ3はＣＨ3Ｏ−ＣＨ2ＣＨ2−またはシクロプロピル、Ａｒ2は４−フロロフェニルまたはピリジルである。）ことを特徴とする請求項１の化合物を製造する方法。(A) reacting a compound of formula 1 with a compound of formula 2 in the presence of a base to produce a compound of formula 3;
Figure 2004528314
 (B) optionally reacting a compound of formula 3 with R 3 NH 2 or Ar 2 NH 2 to produce a compound of formula 4
Figure 2004528314
 (Wherein R 3 is CH 3 O—CH 2 CH 2 — or cyclopropyl, and Ar 2 is 4-fluorophenyl or pyridyl).
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JP2008534518A (en) * 2005-03-25 2008-08-28 サーフェイス ロジックス，インコーポレイティド Improved pharmacokinetic compound
WO2007142323A1 (en) * 2006-06-08 2007-12-13 Ube Industries, Ltd. Novel indazole derivative having spiro ring structure in side chain
JP2012229240A (en) * 2006-12-08 2012-11-22 Irm Llc Compound and composition as protein kinase inhibitors
WO2017150174A1 (en) * 2016-03-04 2017-09-08 株式会社シンスター・ジャパン Pharmaceutical composition containing 2,4-diaminoquinazoline derivative or salt thereof as active ingredient, and 2,4-diaminoquinazoline derivative having specific structure
JPWO2017150174A1 (en) * 2016-03-04 2019-06-13 株式会社 シンスター・ジャパン Pharmaceutical composition containing 2,4-diaminoquinazoline derivative or a salt thereof as an active ingredient, and 2,4-diaminoquinazoline derivative having a specific structure

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ES2280517T3 (en) 2007-09-16
PT1370552E (en) 2007-04-30
UY27225A1 (en) 2002-10-31
MY142915A (en) 2011-01-31
EP1370552B1 (en) 2007-02-14
CY1108041T1 (en) 2013-09-04
US20100249159A1 (en) 2010-09-30
WO2002076977A2 (en) 2002-10-03
EP1370552A2 (en) 2003-12-17
US20030087919A1 (en) 2003-05-08
MXPA03008659A (en) 2005-04-08
TWI336328B (en) 2011-01-21
CA2441501A1 (en) 2002-10-03
DK1370552T3 (en) 2007-05-07
CA2441501C (en) 2010-09-14
AU2002245709A1 (en) 2002-10-08
WO2002076977A3 (en) 2002-12-12
ATE353889T1 (en) 2007-03-15
US20060142314A1 (en) 2006-06-29
HK1061029A1 (en) 2004-09-03
AR035792A1 (en) 2004-07-14
PE20020958A1 (en) 2002-11-14

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